Triazine derivatives

ABSTRACT

NOVEL S-TRIAZINE DERIVATIVES HAVING ANTI-INFLAMMATORY AND ANTI-ATHEROSCLEROTIC ACTIVITY AND OF THE FORMULA   2-R2,4-R1,6-R3-S-TRIAZINE   WHEREIN R1 STANDS FOR PHENETHYLAMINO, ARALKYLAMINO, PYRROLIDINO, PIPERIDINO, 2-KETOPIPERAZINE-4-YL, CYCLOHEXYLAMINO OR STRAIGHT OR BRANCHED HEXYLAMINO; R2 STANDS FOR AMINO, ARALKYLAMINO, PYRROLIDINO, PIPERIDINO 2-KETOPIPERAZINE-4-YL, CYCLOHEXYLAMINO OR STRAIGHT OR BRANCHED HEXYLAMINO; AND R3 STANDS FOR STRAIGHT OR BRANCHED ALKYL OF FROM 1-6 CARBON ATOMS, PYRROLIDINO, PIPERIDINO, 2-KETOPIPERAZINE4-YL OR NR4R5 IN WHICH R4 IS HYDROGEN OR STRAIGHT OR BRANCHED ALKYL OF FROM 1-6 CARBON ATOMS AND R5 IS STRAIGHT OR BRANCHED ALKYL WITH FROM 1-6 CARBON ATOMS, WITH THE PROVISO THAT (A) WHEN R1 IS PHENETHYLAMINO, R2 IS AMINO AND R3 IS STRAIGHT OR BRANCHED ALKYL OF FROM 2-6 CARBON ATOMS; (B) WHEN R1 IS ARALKYLAMINO, PYRROLIDINO, PIPERIDINO OR 2-KETOPIPERAZINE-4-YL, R2 IS THE SAME OR ONE OF SAID GROUPS AND R3 IS STRAIGHT OR BRANCHED ALKYL OF FROM 1-6 CARBON ATOMS; (C) WHEN R1 IS CYCLOHEXYLAMINO OR STRAIGHT OR BRANCHED HEXYLAMINO, R2 IS THE SAME OR ONE OF SAID GROUPS AND R3 IS STRAIGHT OR BRANCHED ALKYL OF FROM 1-6 CARBON ATOMS; AND (D) WHEN R1 IS CYCLOHEXYLAMINO, R2 IS AMINO AND R3 IS PYRROLIDINO, PIPERIDINO, 2-KETOPIPERAZINE-4-YL OR NR4R5, WHEREIN R4 AND R5 HAVE THE ABOVE MEANING.

United States Patent 3,758,471 TRIAZINE DERIVATIVES Tsutomu Irikura,Yasuo Abe, Kyuya Okamura, Kyoichi Higo, Akitoshi Maeda, and F umihikoMorinaga, Tokyo, Japan, assignors to Kyorin Seiyaku Kabushiki Kaisha NoDrawing. Continuation of abandoned application Ser. No. 808,683, Mar.19, 1971. This application June 15, 1971, Ser. No. 153,396

Claims priority, application Japan, Apr. 10, 1968, 43/23,906, 43/23,907;June 6, 1968, 43/318,831; June 28, 1968, 43/44,996

Int. Cl. C07d 55/20, 55/22 U.S. Cl. 260249.6 3 Claims ABSTRACT OF THEDISCLOSURE Novel s-triazine derivatives having anti-inflammatory andanti-atherosclerotic activity and of the formula R stands forphenethylamino, aral-kylamino, pyrrolidino, piperidino,2-ketopiperazine-4-yl, cyclohexylamino or straight or branchedhexylamino;

R stands for amino, aralkylamino, pyrrolidino, piperidino,2-ketopiperazine-4-y1, cyclohexylamino or straight or branchedhexylamino; and

R stands for straight or branched alkyl of from 1-6 carbon atoms,pyrrolidino, piperidino, Z-ketopiperazine- 4-yl or NR R in which R, ishydrogen or straight or branched alkyl of from 1-6 carbon atoms and R isstraight or branched alkyl with from 1-6 carbon atoms, with the provisothat (a) when R is phenethylamino, R is amino and R is straight orbranched alkyl of from 26 carbon atoms;

(b) when R is aralkylamino, pyrrolidino, piperidino or2-ketopiperazine-4-yl, R is the same or one of said groups and R isstraight or branched alkyl of from 1-6 carbon atoms;

(0) when R, is cyclohexylamino or straight or branched hexylamino, R isthe same or one of said groups and R is straight or branched alkyl offrom 1-6 carbon atoms; and

(d) when R is cyclohexylamino, R is amino and R is pyrrolidino,piperidino, 2-ketopiperazine-4-yl or NR R wherein R and R have the abovemeaning.

wherein CROSS-REFERENCE TO PRIOR APPLICATION This is a continuationapplication of Ser. No. 808,683, filed Mar. 19, 1969, now abandoned.

SUMMARY OF THE INVENTION The invention relates to s-triazine derivativesof the formula N F i k a wherem R stands for phenethylamino,aralkylamino, pyrrolidino, piperidino, 2-ketopiperazine-4-y1,cyclohexylamino or straight or branched hexylamino;

R stands for amino, aralkylamino, pyrrolidino, piperidino,2-ketopiperazine-4-yl, cyclohexylamino or straight or branchedhexylamino; and

R stands for straight or branched alkyl of from 1-6 carbon atoms,pyrrolidino, piperidino, Z-ketopiperazine- 4-yl or NR R in which R ishydrogen or straight or branched alkyl of from 1-6 carbon atoms and R isstraight or branched alkyl with from 1-6 carbon atoms, with the provisothat (a) when R is phenethylarnino, R is amino and R is straight orbranched alkyl of from 2-6 carbon atoms;

(b) when R is aralkylamino, pyrrolidino, piperidino or2-ketopiperazine-4-yl, R is the same or one of said groups and R isstraight or branched alkyl of from 1-6 carbon atoms;

(c) when R is cyclohexylamino or straight or branched hexylamino, R isthe same or one of said groups and R is straight or branched alkyl offrom 1-6 carbon atoms; and

(d) when R is cyclohexylamino, R is amino and R is pyrrolidino,piperidino, 2-ketopiperazine-4-y1 or NR R wherein R and R have the abovemeaning.

The invention also embraces the acid addition salts of the compoundswith organic or inorganic acids such as hydrochloric acid, maleic acid,tartaric acid, citric acid and lactic acid.

Activation of the reticuloendothelial system (RES) in mice is remarkablysuppressed by preadministration of a compound having anti-inflammatoryand auti-atherosclerotic activity. Therefore it is found that there is astrong correlation between RES and the compound and this correlation isused as a screening means to determine the utility of the presentinventive compounds. The results of the physiological activities of thepresent inventive compounds by the above method are shown in Table I.

TABLE I Compound of Mean compound Example No.: activity 1 2 129.9 3211.5

The correlation between the results of the above screening and theanti-inflammatory and anti-atherosclerotic activity is explained in acopending application.

The s-triazine derivatives of the present invention exhibitanti-inflammatory and/ or anti-atherosclerotic activity. Further,various cortison-like or oortison-inhibitory activities have also beenobserved in the novel s-tri azine derivatives. The inventive compoundsare therefore not only pharmacologically useful as anti-atherosicleroticagents, but they are also anti-inflammatory agents which may replacesteroidal anti-inflammatory agents.

The compounds of the present invention can be prepared by two processeswhich are represented by the following schemes:

Process A:

wherein X is amino or alkyl and Y and Z are the same or different aminoradicals.

Process B:

RCOOR b/ N W$|1NHC-NH, L I

wherein Wis phenethylamino, R is straight or branched alkyl of from 26carbon atoms and R is lower alkyl.

Example 1.2-methyl-4,6-diphenethylamino-s-triazine A solution ofphenethylamine (4.8 g.) in chloroform (20 ml.) is added in dropwisemanner and under cooling to a solution of2-methyl-4,6-dichloro-s-triazine (3.2 g.) in chloroform (80 ml.). Asolution of potassium icarbonate (8.2 g.) in water (10 m1.) is alsoadded to the reaction mixture. After completing the addition, stirringis continued for some time. The chloroform solution is washed withwater, dried over anhydrous sodium sulfate and concentrated underreduced pressure to yield a crystalline precipitate. The precipitate isrecrystallized from ethanol to yield2-methyl-4,6-diphenethylamino-s-triazine as colorless crystals, M.P.213-214 C. The yield is 1.0 g.

Analysis.--Calcd. for C H N (percent): C, 72.04; H, 6.95; N, 21.01.Found (percent): C, 72.18; H, 7.08; N, 21.12.

Example 2.-2-n-butyl-4,G-diphenethylamino-s-triazine Phenethylamine (9.7g.) is added, with stirring, to a mixture of2-n-butyl-4,6-dichloro-s-triazine (4.2 g.) in water (100 ml.). Themixture is slowly heated to reflux, and the refluxing temperature ismaintained for 2 hours. After cooling, the product is collected byfiltration and recrystallized from acetonitrile to give2-n-butyl-4,6-diphenethylamino-s-triazine as colorless needles, M.P. 66-67" C. The yield is 4.0 g.

Analysis.-Calcd. for C H N (percent): C, 73.56; H, 7.78; N, 18.65. Found(percent): C, 73.00; H, 7.80; N, 18.69.

Example 3.-2-methyl-4,6-dicyclohexylamino-s-triazine Cyclohexylamine(8.0 g.) is added, with stirring, to a mixture of2-methyl-4,6-dichloro-s-triazine (3.2 g.) in Water (100 ml.). Themixture is slowly heated to reflux, and the refluxing temperature ismaintained for 2 hours. After cooling, the product is collected byfiltration and recrystallized from ethyl acetate to give2-methyl-4,6-dicyclohexylamino-s-triazine as colorless needles, M.P.187- 189 C. The yield is 3.7 g.

4 Analysis.Calcd. for C H N (percent): C, 66.39; H, 9.40; N, 24.21.Found (percent): C, 66.23; H, 9.29; N, 23.05.

Example 4.2-n-butyl-4,6-dicyclohexylamino-s-triazine The compound isobtained by following the same process as in Example 3, except that2-n-butyl-4,6-dichloro-striazine (4.2 g.) is employed instead of2-methyl-4,6-dichloro-s-triazine. Recrystallization from n-hexane yields3.0 g. of the compound, M.P. l36137 C.

Analysis.Calcd. for C H N (percent): C, 68.84; H, 10.03; N, 21.13. Found(percent): C, 69.35; H, 10.17; N, 21.14.

Example 5.2-methyl-4,6-dipyrrolidino-s-triazine The compound is obtainedby following the same process as in Example 1. Recrystallization frompetroleum ether yields 1.0 g. of the compound, M.P. 83-85 C.

Analysis.-Calcd. for C H N (percent): C, 61.77; H, 8.21; N, 30.02. Found(percent): C, 61.53; H, 8.11; N, 30.35.

Example 6.2-methyl-4,6-di(2-ketopiperazine- 4-yl)-s-triazine Thecompound is obtained by following the same process as in Example 2.Recrystallization from ethanol yields 1.0 g. of the compound, M.P. 303C. (dec.).

Analysis.Calcd. for C H N 0 (percent): C, 49.47; H, 5.88; N, 33.66.Found (percent): C, 49.18; H, 5.87; N, 34.34.

Example 7.2-methyl-4,6-dipiperidino-s-triazine The compound is obtainedby following the same process as in Example 1. Recrystallization frompetroleum ether yields 1.2 g. of the compound, M.P. 81-83" C.

Analysis.-Calcd. for C H N (percent): 0, 64.33; H, 8.87; N, 26.80. Found(percent): C, 64.09; H, 8.70; N, 27.19.

Example 8.2-methyl-4-pyrrolidino-6-phenethylamino s-triazine Example9.-2-methyl-4-phenethylamino-6-(2-ketopiperazine-4-yl)-s-triazine Thecompound is obtained by following the same process as in Example 8.Recrystallization from ethanol yields 10.0 g. of the compound, M.P.231-233 C.

Analysis.-Calcd. for C H N O (percent): C, 61.52; H, 6.45; N, 26.91.Found (percent): C, 61.14; H, 6.38; N, 26.32.

Example 10.-2-methyl-4,6-di-n-hexylamino-s-triazine The compound isobtained by following the same process as in Example 2.Recrystallization from ethyl acetate yields 3.0 g. of the compound, M.P.154-155 C.

Analysis.-Calcd. for C H N (percent): C, 65.48; H, 10.65; N, 23.87.Found (percent): C, 65.61; H, 10.60; N, 23.84.

Example 11.-2-n-butyl-4,6-di-n-hexylamino-s-triazine The compound isobtained by following the same process as in Example 2.Recrystallization from ethyl acetate yields 1.0 g. of the compound, M.P.97-98 C.

Analysis.-Calcd. for C H N (percent): C, 68.01; H, 11.12; N, 20.87.Found (percent): C, 67.90; H, 11.03; N, 20.76.

Example 12.-2-amino-4-cyclohexylamino-6- piperidino-s-triazinePiperidine (5.1 g.) is added, with stirring, to a mixture of2-amino-4-cyclohexylamino-6-chloro-s-triazine (6.8 g.) in water (150ml.). The mixture is slowly heated to reflux and the refluxingtemperature is maintained for 2.5 hours. After cooling, the reactionmixture is extracted with chloroform, and the chloroform solution iswashed with water, dried over anhydrous sodium sulfate and concentratedunder reduced pressure to give a syrup which is treated withethanol-water to yield a crystalline precipitate. The precipitate iscollected by filtration and recrystallized from 60% ethanol to give thecompound as colorless needles, M.P. 123-127 C. Yield is 3.0 g.

Analysis.-Calcd. for C H N (percent): C, 60.84; H, 8.75; N, 30.41. Found(percent): C, 60.31; H, 8.64; N, 30.48.

I Example 13.2-amino-4-cyclohexy1amino-6-(Z-ketdpiperazine-4-yl)-s-triazine A solution of 2-ketopiperazine (5.4 g.) inwater (50 ml.) is added, with stirring, to a mixture of 2-amino-4-cyclohexylamino-6-chloro-s-triazine (6.1 g.) in water (150 ml.). Themixture is slowly heated to reflux and the refluxing temperature ismaintained for 3 hours. After cooling, the product is collected byfiltration and recrystallized from ethanol to give2-amino-4-cyclohexylamino-6-(2- ketopiperazine-4-yl)-s-triazine ascolorless crystals, M.P. 266-269 C. Yield is 2.3 g.

Analysis.Calcd. for C13H21N70 (percent): C, 53.59; H, 7.27; N, 33.66.Found (percent): C, 53.80; H, 7.37; N, 34.02.

Example 14.2-ethyl-4,6-diphenethylamino-s-triazine The compound isobtained by following the same process as in Example 2, except that2-ethyl-4,6-dichloro-striazine (3.6 g.) is employed instead of2-n-butyl-4,6- dichloro-s-triazine. Recrystallization from acetonitrileyields 4.4 g. of the compound, M.P. 147-148 C.

Analysis.Calcd. for C H N (percent): C, 72.59; H, 7.25; N, 20.16. Found(percent): C, 72.45; H, 7.11; N, 20.26.

Example 15.2-n-propyl-4,6-diphenethylaminos-triazine The compound isobtained by following the same process as in Example 2, except that2-n-propyl-4,6-dichloros-triazine (3.8 g.) is employed instead of2-n-butyl-4,6- dichloro-s-triazine. Recrystallization from acetonitrileyields 5.9 g. of the compound, M.P. 96-97 C.

Analysis.Calcd. for C H N (percent): C, 73.09; H, 7.53; N, 19.38. Found(percent): C, 73.08; H, 7.35; N, 19.23.

Example 16.2-isopropyl-4,6-diphenethylamino-striazine I The compound isobtained by following the same process as in Example 2, except that2-isopropyl-4,6-dichloros-triazine (3.8 g.) is employed instead of2-n-butyl-4,6- dichloro-s-triazine. Recrystallization from acetonitrileyields 5.0 g. of the compound, M.P. 90-91 C.

Analysis.-Calcd. for C22H2'1N5 (percent): C, 73.09; H, 7.53; N, 19.38.Found (percent): C, 72.98; H, 7.59; N, 19.04.

Example 17.-2-ethyl-4,6-dicyclohexylamino-s-triazine The compound isobtained by following the same process as in Example 3, except that2-ethyl-4,6-dichloro-striazine (3.6 g.) is employed instead of2-methyl-4,6-dichloro-s-triazine. Recrystallization from acetonitrileyields 4.5 g. of the compound, M.P. 179 C.

6 Analysis.-Calcd. for C H N (percent): C, 67.29; H, 9.63; N, 23.08.Found (percent): C, 67.27; H, 9.60; N, 23.17.

Example 18.2-n-propyl-4,6-dicyclohexylaminos-triazine The compound isobtained by following the same process as in Example 3, except that2-n-propyl-4,6-dichloros-triazine (3.8 g.) is employed instead of2-methyl-4,6- dichloro-s-triazine. Recrystallization from acetonitrileyields 4.3 g. of the compound, M.P. 145146 C.

Analysis.-Calcd. for C H N (percent): C, 68.10; H, 9.84; N, 22.06. Found(percent): C, 67.85; H, 9.73; N, 22.06.

Example 19.-2-isopropyl-4,6-dicyclohexylaminos-triazine The compound isobtained by following the same process as in Example 3, except that2-isopropyl-4,6-dichloros-triazine (3.8 g.) is employed instead of2-methyl-4,6- dichloro-s-triazine. Recrystallization from acetonitrileyields 5.5 g. of compound, M.P. 149-150 C.

Analysis.--Calcd. for C H N (percent): C, 68.10; 113, 9.84; N, 22.06.Found (percent): C, 68.07; H, 9.85;

Example 20.2-n-hexyl-4,6-dicyclohexylamino-s-triazine The compound isobtained by following the same process as in Example 3, except that2-n-hexyl-4,6-dichloro-striazine (4.7 g.) is employed instead of2-methyl-4,6-dichloro-s-triazine. Recrystallization from acetonitrileyields 6.3 g. of the compound, M.P. 114 C.

Analysis.Calcd. for C H N (percent): C, 70.15; H, 10.37; N, 19.48. Found(percent): C, 70.18; H, 10.32; N, 19.60.

Example 21.-2-amino-4-phenethylamino-6-ethyl-striazinePhenethylbiguanide hydrochloride (24.1 g.) is added to a solution ofsodium (2.3 g.) methanol and sodium chloride formed is removed byfiltration. To the filtrate is added, with stirring, ethyl propionate(10.2 g.) under cooling (40 C.). The mixture is stirred at roomtemperature for 4 hours and treated with water (800 ml.). On standingseveral days, the product is collected by filtration and recrystallizedfrom isopropylalcohol to give 2-amino-4-phenethyl-6-ethyl-s-triazine ascolorless prismatic crystals, M.P. 140.5-142 C. Yield is 11.4 g.

Analysis.Calcd. for C H N (percent): C, 64.17; H, 7.04; N, 28.79. Found(percent): C, 64.07; H, 7.12; N, 28.59.

Example 22.2-amino-4-phenethylamino-6-n-propyl-striazine The compound isobtained by following the same process as in Example 21, except thatethyl butylate (15.0 g.) is employed instead of ethyl propionate.Recrystallization from isopropanol yields 12.2 g. of the compound, M.P.8991 C.

Analysis.Calcd. for C H N (percent): C, 65.34; H, 7.44; N, 27.22. Found(percent): C, 64.94; H, 7.77; N, 2709.

Example 23 .2-amino-4-phenethylamino-6-isopropyl-striazine The compoundis obtained by following the same process as in Example 21, except thatethyl isobutylate (15.0 g.) is employed instead of ethyl propionate.Recrystallization from acetonitrile yields 12.2 g. of the compound, M.P.-81 C.

Analysis.Calcd. for C H N (percent): C, 65.34; H, 7.44; N, 27.22. Found(percent): C, 65.12; H, 7.36; N, 27.57.

Example 24.2-amino-4-phenethylamino-6-n-butyl-striazine The compound isobtained by following the same process as in Example 21, except thatethyl valerate (17.0 g.) is employed instead of ethyl propionate.Recrystallization from isopropanol yields 13.4 g. of the compound, M.P.93-95 C.

Analysis.Calcd. for C H N (percent): C, 66.39; H, 7.80; N, 25.18. Found(percent): C, 65.70; H, 7.68; N, 25.90.

Example 25.-2-amino-4-phenethylamino 6-isobutyl-striazine The compoundis obtained by following the same process as in Example 21.Recrystallization from isopropanol yields 11.3 g. of the compound, M.P.109-1105 C.

Analysis.Calcd. for C H N (percent): C, 66.39; H, 7.80; N, 25.81. Found(percent): C, 66.19; H, 7.86; N, 26.06.

Example 26.2-'amino-4cyclohexylamino-G-methylamino-s-triazine 40%methylamine (4.7 g.) is added, with stirring, to a mixture of2-amino-4-cyclohexylamino-6-chloro-s-triazine (6.8 g.) in water (150ml.). The mixture is slowly heated to reflux and the refluxingtemperature is maintained for 2 hours. After cooling, the product iscollected by filtration and recrystallized from acetonitrile to give thecom pound as white crystals, M.P. 189-190 C. Yield is 4.9 g.

Analysis.Calcd. for C H N (percent): C, 54.03; H, 8.16; N, 37.81. Found(percent): C, 54.12; H, 8.25; N, 37.94.

Example 27.-2-amino-4-1cyclohexylamino-6-ethy1- amino-s-triazine maleate70% ethylamine (3.9 g.) is added, with stirring, to a mixture of 2 amino4 cyclohexylamino 6 chloro-striazine (6.8 g.) in water (150 ml.). Themixture is slowly heated to reflux and the refluxing temperature ismaintained for 2 hours. After cooling, the reaction mixture is extractedwith ethyl acetate and the ethyl acetate solution is washed with water,dried over anhydrous sodium sulfate and concentrated under reducedpressure to give a syrup. The syrup is dissolved in methanol (20 ml.),added to a solution of maleic acid (2.3 g.) in methanol (10 ml.) and themixture is refluxed for 1 hour to yield a crystalline precipitate. Theprecipitate is collected by filtration and recrystallized from ethanolto give the compound as white crystal-powder, M.P. 160161 C. Yield is3.6 g.

Analysis.Calcd. for C H N O (percent): C, 51.12; H, 6.87; N, 23.85.Found (percent): C, 51.20; H, 6.86; N, 23.63.

Example 28.2-amino-4-cyclohexylamino-6-n-propylamino-s-triazine maleateThe compound is obtained by following the same process as in Example 27.Recrystallization from acetonitrile yields 4.5 g. of the compound, M.P.169-170 C.

Analysis.Calcd. for C H N O (percent): C, 52.44; H, 7.15; N, 22.94.Found (percent): C, 52.57; H, 7.29; N, 22.96.

Example 29.-2-amino-4-cyclohexylamino-6-n-butylamino-s-triazine maleateThe -compound is obtained by following the same process as in Example27. Recrystallization from methanol yields 3.7 g. of the compound, M.P.156158 C.

Analysis.Calcd. for C H N O (percent): C, 53.66; H, 7.42; N, 22.09.'Found (percent): C, 53.62; H, 7.55; N, 22.16.

Example 30.2-amino-4-cyclohexylamino-6-dimethy1- amino-s-triazinemaleate The compound is obtained by following the same process as inExample 13. Recrystallization from lacetonitrile yields 5.2 g. of thecompound, M.P. 134-136" C.

Analysis.Calcd. for C H N (percent): C, 55.90; H, 8.53; N, 35.57. Found(percent): C, 55.97; H, 8.69; N, 35.27.

Example 31.-2-amino-4-cyclohexylamino-6-diethylamino-s-triazine maleateThe compound is obtained by following the same process as in Example 27.Recrystallization from acetonitrile yields g. of the compound, M.P.167169 C.

Analysis.Calcd. for C17H28N6O4 (percent): C, 53.66; H, 7.42; N, 22.09.Found (percent): C, 53.66; H, 7.26; N, 22.06.

Example 32.-2-amino-4-cyclohexylamino-6-di-npropylamino-s-triazinemaleate The compound is obtained by following the same process as inExample 27. Recrystallization from acetonitrile yields 5.0 g. of thecompound, M.P. 132 C.

AnaIysis.--Calcd. for C H N O (percent): C, 55.86; H, 7.90; N, 20.58.Found (percent): C, 55.50; H, 7.96; N, 20.69.

Example 33.-2-amino-4-cyclohexylamino-6-di-nbutylamino-s-triazinemaleate References Cited UNITED STATES PATENTS 2,909,420 10/1959 Gysinet al. 260-249.9 X 2,909,421 10/1959 Gysin et al. 260-249.6 X

JOHN M. FORD, Primary Examiner US. Cl. X.R.

